The present invention is in the area of bioerodible controlled release systems or the delivery and administration of labile proteins and peptides.
The concept of using biodegradable matrix systems for the delivery of drugs and therapeutically active agents has been well developed and demonstrated to be clinically useful. A number of methods have been well established for the controlled release of low molecular weight compounds. However, the delivery of high molecular weight compounds, such as biologically active proteins and peptides has been difficult with the presently investigated hydrophilic or hydrophobic, non-polymeric or polymeric matrices.
Alternative methods or carriers for delivery which correct the deficiencies in these systems have been sought for years. Bioerodible polymeric matrices have shown promise in the development of improved delivery systems. Several polymers have been used, including poly(lactides) and their copolymers with glycolic acid, poly(orthoesters), ethylene vinyl acetate and poly(anhydrides). Ethylene vinyl acetate has worked well for the release of biologically active proteins, but is not practical because it is non-degradable. Poly(lactide/co-glycolide) has not shown much promise because there is a considerable amount of aggregation and denaturation of the protein within the matrix. Poly(anhydrides) and poly(orthoesters) release proteins or peptides, but the release rates and the duration of release obtained were not acceptable.
It would be particularly desirable to develop a microparticulate controlled release delivery system for controlled delivery of biologically active proteins. An example of a biologically active and useful protein that is most effective when delivered continuously over extended periods of time is growth hormone. Unfortunately, this protein frequently aggregates, denatures and loses activity, within the matrix or during the preparation of the delivery system, making it difficult to deliver on a continuous basis.
A controlled release polymer implant system that has been developed to deliver growth hormone is described in European Patent Application Publication No. 210 039B which discloses a sustained release microcapsule that contains the protein or peptide, an organic base substance as a drug retaining substance, and wherein the microcapsule wall is made of a polymer. This system has several drawbacks. For example, because the device is not biodegradable, the device must be removed after treatment. Furthermore, the polymer utilized to form the device is limited to those which do not bind to nor promote aggregation of the protein. This limitation in the choice of the polymer also limits the range, type and extent of release of active agent. Polymers which might otherwise be desirable for reasons of release kinetics and duration, specifically polymers that are more hydrophilic or hydrophobic in nature, cannot be used due to interactions with, or adverse influence upon, the biologically active protein. The device is also limited to subcutaneous implantation in animals since use in humans would require post treatment removal of the device.
It is therefore an object of the present invention to provide a biodegradable controlled release microparticulate, injectable delivery system for controlled in vivo administration of proteins such as growth hormone.
It is another object of the present invention to provide a method of manufacturing a microparticulate injectable delivery system.
It is yet another object of the present invention to provide a method and means for stabilizing proteins such as growth hormone in biodegradable drug delivery systems, as well as a method of manufacturing a microparticulate injectable delivery system capable of delivering stabilized protein in the biologically active form.
It is still a further object of the present invention to provide a method and means for modulating the rate of release of the parent or stabilized polypeptidic agents from the microparticulate drug delivery system.